臺灣博碩士論文加值系統

酸棗仁湯為臨床上最常使用用於治療失眠的中藥方劑，而中草藥面臨許多問題如品質管制、多成份分析以及潛在中西藥合併使用造成交互作用的影響。本實驗以酸棗仁湯為主要研究方劑，研究分兩大部分，第一部分主要建立靈敏性、選擇性較高的高效液相層析串聯式質譜儀分析方法，針對酸棗仁湯七種活性成分: jujuboside A、jujuboside B、spinosin、mangiferin、ferulic acid 、pachymic acid及glycyrrhizic acid，應用於市售科學中藥有效成分進行比對分析，可做為臨床用藥的參考。利用此分析方法更進一步探討各成份於大鼠體內血中濃度變化情形及藥物動力學變化。本研究使用清醒且自由移動的大鼠(freely-moving rat model)，口服給予酸棗仁湯後，靜脈連續採血12小時，以甲醇蛋白質沉澱法處理後，注入高效液相層析串聯式質譜儀偵測系統中分析，由藥物動力學結果，可以探討酸棗仁湯中活性成分的濃度變化情形。mangiferin為酸棗仁湯中含量高的活性指標成分，實驗延伸探討單一藥材及複方對於mangiferin之藥物動力學影響，是否存在藥材成份與成份間的交互作用。實驗延伸的第二部分，已知西藥唑比坦(zolpidem)普遍用於治療失眠，而酸棗仁湯也是中醫普遍使用治療失眠的傳統名方，在健保資料庫的研究發現兩者很常併用，但中西藥併用的安全性及潛在交互作用可能會影響治療療效。本研究以藥物動力學的角度探討給予大白鼠酸棗仁湯後，是否影響唑比坦於血中的藥物濃度變化，以及是否影響大白鼠縮短進入睡眠的時間及睡眠時間。本研究利用高效液相層析儀結合螢光偵測器，建立唑比坦之分析條件( 回收率、分析確效等)。使用清醒且自由移動的大鼠(freely-moving rat model)，口服給予酸棗仁湯五天後，給予唑比坦後靜脈連續採血四小時，以乙酸乙酯液相萃取後，注入高效液相層析儀系統中分析，由結果顯示口服給予正常劑量及高劑量的酸棗仁湯與對照組之間唑比坦於藥物動力學無顯著差異。利用戊巴比妥誘導的翻正反射藥理實驗結果顯示，正常劑量的酸棗仁湯和唑比坦併用可以有效縮短進入睡眠時間，此結果可以做為臨床用藥參考。

Suan-Zao-Ren decoction (SZRD) is one of the most popular traditional Chinese medicine prescriptions for the treatment of restlessness, anxiety and insomnia. Nowadays, TCMs faced on some difficulties, such as quality control of herbs, multi- component analysis, less evidence base for clinical use, and the potential impact of Chinese and Western medicine combined interactions. In this thesis, the main research about SZRD study into two parts, the first part is to develop a comprehensive analytical method by using liquid chromatography with tandem mass spectrometry(LC-MS/MS)for simultaneous quantification of seven main bioactive components, ie., jujuboside A, jujuboside B, spinosin, mangiferin, ferulic acid, pachymic acid and glycyrrhizic acid. The established analytical method has been extended to quantitate and compare in different brands of commercially available SZRD successfully. Furthermore, this method was applied to investigate the pharmacokinetics of bioactive components of SZRD in conscious and freely moving rat by collecting blood sample. These pharmacokinetic results provide a constructive contribution to better understand the absorption mechanism of SZRD and to support additional clinical evaluation. Besides, mangiferin is one of the main active flavonoid components of Anemarrhenae Rhizoma and SZRD and was worth further pharmacokinstic study. This validated method was also applied to a comparative study on the pharmacokinetics and bioavailability of mangiferin following administration of mangiferin (a single compound), Anemarrhenae Rhizoma extracts (single herbal extract), and Suan-Zao-Ren decoction (SZRD; a multiple herbal extract). Prescription compatibility and other components of Anemarrhenae Rhizoma were significantly altered by the pharmacokinetics of mangiferin. The phenomenon may due to herbal ingredient-ingredient or herb-herb interaction.
The second part of the experiment, according to National Health Insurance in Taiwan research, the western medicine of zolpidem has been a commonly prescribed pharmaceutical for insomnia treatment. SZRD is one of the most popular traditional Chinese medicine prescriptions for the treatment of insomnia. Since there is concern about the potential clinical treatment efficacy, the herb-drug interaction between SZRD and zolpidem is investigated using the well established pharmacokinetic animal model and pentobarbital-induced loss of righting reflex model. This study develops a validated high-performance liquid chromatography (HPLC) with fluorescence detection system to monitor zolpidem in rat plasma for additional evaluation of herb-drug interaction. After oral administration of SZRD for five days, the zolpidem was given intragastrically. Then, blood samples were collected for four hours and the plasma samples were pretreated by liquid-liquid extraction with ethyl acetate and then injection into high performance liquid chromatography systems for analysis. The results showed no significant difference between the pharmacokinetics of normal dose oral administration of high-dose and control. Pentobarbital-induced loss of righting reflex pharmacological experiments show that the combination of normal dose SZRD and zolpidem a can shorten sleep latency, this result can be used as a reference for clinical use.

附表目錄 V
附圖目錄 VI
英文摘要 VII
摘要 IX
第一章 緒論 1
第一節 失眠 1
一、 失眠的定義 1
二、 失眠的分類 1
三、 失眠的西醫治療 1
四、 失眠的中醫理論 2
五、 失眠的中醫治療 3
六、 失眠的流行病學研究 3
第二節 酸棗仁湯 4
一、 酸棗仁湯簡介 4
二、 酸棗仁之主要活性成分與現代藥理研究 5
第三節 唑比坦(Zolpidem) 6
一、 唑比坦(Zolpidem)介紹 6
二、 藥物交互作用 7
第四節 層析法 8
一、 層析法之概述: 8
二、 高效液相層析法(HPLC) 8
三、 質譜法Mass Spectrometry 8
第五節 分析方法確效: 10
一、 選擇性selectivity: 10
二、 準確度(accuracy)及精確度(precision) 10
三、 基質效應(matrix effect)及回收率(recovery) 11
四、 線性關係與靈敏性 11
五、 安定性(Stability) 11
第五節 藥物動力學 12
一、 藥物動力學之概述 12
二、 藥物動力學之模式 13
三、 藥物動力學之參數 15
四、 線性藥物動力學以及非線性藥物動力學 18
第六節 藥物效力學 19
一、 藥物效力學概述 19
二、 翻正反射 19
第二章 研究動機與目的 20
第三章 實驗材料與研究方法 21
第一節、 實驗材料 21
一、 化學試藥 21
二、實驗儀器 22
三、 實驗動物 23
第二節、 酸棗仁湯之分析方法開發 23
一、 酸棗仁湯萃取及知母製備 23
二、 高效液相層析串聯質譜儀(UHPLC-MS/MS) 24
三、 標準品檢量線配置 25
四、 酸棗仁湯活性成分定量方法 25
第三節、 酸棗仁湯於大白鼠體內之藥物動力學 26
一、 標準品於大白鼠血漿之檢量線配置 26
二、 動物實驗模式—清醒狀態下動物模式 26
三、 藥物動力學分析 28
第四節、 酸棗仁湯對於唑比坦藥物動力學及藥物效力學影響 28
一、 高效液相層析儀之分析條件 28
二、 檢量線的配置及高效液相層析儀之方法確效 28
三、 藥物動力學動物模式及實驗設計 29
四、 翻正反射模式 30
第五節、 統計方法 31
第四章實驗結果 32
第一節 酸棗仁湯活性成分分析及大白鼠體內之藥物動力學研究 32
一、 高效液相層析串聯質譜儀 (HPLC-MS/MS) 之分析條件 32
二、 高效液相層析串聯質譜儀(UHPLC-MS/MS)之分析方法確效 33
三、 分析方法應用-科學中藥定量 35
四、 酸棗仁湯各種活性成份之藥物動力學 35
五、 單方複方的比較 36
第二節 酸棗仁湯對於唑比坦在藥物動力學之交互作用影響 36
一、 高效液相層析儀之唑比坦分析條件 36
二、 層析系統之分析方法確效 37
三、 酸棗仁湯對於唑比坦之藥物動力學影響 38
四、 翻正反射 38
第五章討論 40
第一節、 酸棗仁湯對於唑比坦在藥物動力學及藥物效力學之交互作用影響 40
一、 酸棗仁湯活性成分之分析方法 40
二、 酸棗仁湯活性成分之含量分析與應用 41
三、 酸棗仁湯於大鼠體內之藥物動力學探討 42
四、 單一成分、單一藥材與複方對於知母苷的藥物動力學影響 43
第二節、 酸棗仁湯對於唑比坦在藥物動力學及藥物效力學之交互作用影響 44
一、 唑比坦的分析方法 44
二、 草藥-藥物交互作用中唑比坦之藥物動力學及藥物效力學研究 45
第七章 結論 47
第八章 參考資料 48
附表 57
附圖 67

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